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Spontaneous Regression of Hepatocellular Carcinoma after
Eradication of HCV

Eric F. Martin1, Michael Huang2, Beatrice Madrazo3 and Cynthia Levy1*

1Division of Hepatology, University of Miami Miller School of Medicine, Miami, Florida, USA
2Division of Gastroenterology, University of Miami Miller School of Medicine, Miami, Florida, USA
3Division of Radiology, University of Miami Miller School of Medicine, Miami, Florida, USA

Spontaneous regression of Hepatocellular Carcinoma (HCC) is
uncommon. Several factors have been suggested as the mechanisms
behind spontaneous regression of HCC, namely reduction in blood
supply, inflammation, and immunological factors; however, the
precise pathogenesis is unknown. We present a case of spontaneous
regression of HCC in a 57 year old female with cirrhosis secondary to
chronic Hepatitis C Virus (HCV). On a triple phase CT scan of the liver,
she was found to have a 26 mm liver lesion fulfilling Liver Imaging
Reporting and Data Systems (LI-RADs) 5 criteria for HCC with
elevated serum Alpha Fetoprotein (AFP) level to 218 ng/mL. She was
started on sofosbuvir and simeprevir for treatment of HCV, genotype
1b. HCV RNA was undetectable by week four of treatment and she
successfully completed 12 weeks of therapy. Repeat triple phase
CT scan of the liver one month after completing anti-HCV therapy,
aforementioned liver lesion reduced to 6 mm x 5 mm. Serum AFP also
decreased from 218 ng/mL before treatment to 37 ng/mL during
treatment and to 22 ng/mL after treatment. Spontaneous regression
of HCC with anti-HCV therapy and successful HCV eradication is new
and previously unexplained.

Hepatocellular Carcinoma (HCC) is the most common cause
of primary liver cancer and the fifth most common cancer
worldwide. Although early detection and development of
therapies for HCC often improve prognosis, the prognosis of
untreated, advanced HCC remains poor with a median survival
of less than six months. Spontaneous regression of HCC is rare
with a reported incidence rate of 1 in 140,000 cases of HCC [1].
HCC regression is generally defined as the partial or complete
regression of HCC in the absence of specific anti-neoplastic
therapy, namely chemotherapy and/or locoregional therapy.
The underlying mechanism of HCC regression, however, remains
unknown. HCC regression following antiviral therapy for chronic
HCV, specifically with sofosbuvir, has not been previously
reported. Further understanding of this phenomenon could lead
to novel strategies for HCC treatment. We report here one case of spontaneous regression of HCC following treatment of chronic
HCV with sofosbuvir and simeprevir.

Case Report

A 57 year old black female with Child-Pugh A cirrhosis
secondary to chronic HCV, genotype 1b, was seen in the
Hepatology clinic. She is a non-responder to a previous 6-month
treatment course of Pegylated interferon-2α and Ribavirin.
Previous surveillance abdominal imaging, which included
ultrasonography, triple phase CT scan of the liver, and MRI
abdomen with and without contrast, showed no evidence of
HCC. The last imaging was an MRI of the
abdomen with and without contrast in July 2012 that showed
no evidence of hepatocellular carcinoma, but did reveal multiple
small intrahepatic lesions with delayed contrast pooling
suggestive of regenerative nodules. The serum AFP level at this
time was elevated at 218 ng/mL, which was previously 71 ng/
mL. Follow-up triple phase CT scan of the liver in January 2014
revealed a 26 mm x 18 mm lesion in segment VII fulfilling LI-RADS
5 criteria, which was highly suggestive of HCC. AFP at that time
was 196 ng/mL. She was referred to the liver transplant clinic
where she was started on anti-HCV treatment with sofosbuvir
400 mg/day and simeprevir 150 mg/day with recommendations
to proceed with an evaluation for liver transplantation. When
treatment was initiated in February 2014, her HCV RNA was 1
million IU/mL. By week 4, HCV RNA became undetectable and
remained so throughout the 12-week course of sofosbuvir and
simeprevir, which she completed in May 2014.

Of note, during the transplant evaluation she was diagnosed
with latent tuberculosis by positive QuantiFERON-TB Gold
test and negative chest X-ray. In May 2014, she was started on
isoniazid 900 mg/day for an anticipated nine months. Repeat
triple phase CT scan of the liver in April 2014 demonstrated the
lesion measured 13 mm (compared to 26 mm 3 months earlier).
Her AFP also decreased from 196 ng/mL to 37 ng/mL. Finally,
follow-up triple phase liver CT scan in July 2014 showed that the
lesion in segment VII had reduced to mere 6 mm x 5 mm with an
AFP of 22 ng/mL. Figure 1 demonstrates the regression of HCC in this patient before starting sofosbuvir and simeprevir (Figure
1A-C) and after finishing sofosbuvir and simeprevir (Figure 1DF).
Table 1 shows the trend of HCV RNA, AFP, and the size of the
liver mass at initial visit, during HCV treatment, and at last visit.

Discussion

Spontaneous regression of HCC is a rare happening, yet the
true incidence is difficult to accurately define. Upon reviewing
10 randomized controlled trials including 1640 patients with
HCC, Oquiñena et al. [2] estimated the incidence of spontaneous
regression of HCC to be 0.4%. The number of cases of spontaneous
regression of HCC reported in the literature is higher in HCC than
in other malignancies, which likely reflects a higher incidence of
HCC compared to other malignancies. Although a large majority
of the previously reported cases involves partial regression, few
cases describe complete regression of HCC [3]. There are even
case reports of complete spontaneous regression of HCC with
metastasis to the chest wall [4], portal vein tumor thrombus
[5], and pulmonary metastases [6]. In the event of the portal vein tumor thrombus and pulmonary metastases, both patients
experienced chronic HCV. To our knowledge, no previous cases
of HCC regression coinciding with anti-HCV therapy have been
reported.

No evidence exists to support a correlation between the
underlying etiology of liver disease and spontaneous regression
of HCC. One of the largest and most recent reviews of the literature
by Oquiñena et al. [7] included 59 clinical reports of spontaneous
regression of HCC. The clinical profile and demographics varied
widely in their cohort of patients. A plausible explanation for the
pathogenic mechanism underlying HCC regression was offered
in 27 of the 59 cases (46%). Of those identified, ischemia due to
hemorrhagic shock or hepatic artery thrombosis was the most
commonly detected cause, occurring in 10 of 59 cases (17%).
Several other factors, namely inflammation, immunological
factors, and reduction in blood supply leading to tumor
hypoxia have also been suggested as likely mechanisms behind
spontaneous regression of HCC, but the precise pathogenesis is unknown [3,8].

Table 1:The trend of HCV RNA, AFP, and the size of the liver mass at initial visit, during HCV treatment and at last visit.

In a more recent systematic review of 75
patients with spontaneous remission of HCC, the cause of
regression was attributed to tumor hypoxia in 21 (28%) and
systemic inflammatory response in 25 (33%) patients while
the cause of HCC regression of the remaining 29 (38%) patients
were unknown [9]. Recognized causes of tissue hypoxia include
spontaneous hepatic artery thrombosis, an occlusive portal
vein thrombosis, development of a large arterioportal shunt,
angiospasm during angiography, and prolonged hypotension
due to massive gastrointestinal bleeding. Tumor hypoxia as a
mechanism for HCC regression seems intuitive as it is the basis
of established treatment options for HCC, namely Transhepatic
Arterial Chemoembolization (TACE) and the oral multiple kinase
inhibitor sorafenib. TACE occludes the arterial supply to the
tumor, which effectively reproduces the effect of HCC regression
that has been reported after spontaneous arterial thrombosis [10-
12]. Likewise, sorafenib relies upon induction of tumor hypoxia
due to its anti-angiogenesis effect. It is possible that the presence
of an arterioportal shunt near the liver tumor may alter the
dynamics of blood flow to the tumor, which is essential for tumor
growth. Similar to TACE, tumor infarction due to disruption of the
feeding vessel due to subintimal injury and tumor invasion could
produce tumor hypoxia leading to tissue necrosis and regression
of HCC. Rapid tumor growth, administration of vitamin K,
abstinence from alcohol, consumption of herbal medicines, high
fevers, and gastrointestinal bleeding have also been suggested as
factors causing spontaneous regression of HCC [13]. Of note, our
patient had no radiographic evidence of an arterioportal shunt or
spontaneous hepatic artery or portal vein thrombosis.

Perhaps most compelling are the immunological factors that
have been implicated in the spontaneous regression of HCC. For
over three decades, it has been proposed that the most important
factor in spontaneous regression of cancer is stimulation of the
immune process [14]. It was previously shown that patients
with HCC, particularly those with chronic HCV, had significant
impairment in T-cell responses at baseline, which correlated
with tumor burden and poor outcome [15]. A previous report
demonstrated that treatment with activated T-lymphocytes after
surgery reduced the recurrence rates of HCC, suggesting that HCC
regression may be associated with the host immune response
[16]. In a cohort of liver transplant recipients, those who achieved
eradication of HCV after antiviral therapy achieved restoration of
HCV-specific T-cell responses. On the other hand, patients with
progressive HCV recurrence after liver transplant that failed
antiviral therapy demonstrated declining frequencies of HCVspecific
T-cells [17]. Similarly, in a cohort of coinfected patients
with HCV and HIV who were treated with Highly-Active Anti-
Retroviral Therapy (HAART), HCV Ab-reactivity was associated
with an inferior virologic response to HAART compared to
HCV Ab-negative patients [18]. It is possible that HCV lowers
CD4+ T-cell recovery through direct pathogenic effect on the
lymphocytes. It has also been hypothesized that CD4+ T-cell
depletion results from ongoing cell activation and apoptosis
drive by HCV [19]. The studies present data that strongly support
the theory of immune reconstitution following eradication of
HCV, which may represent the immunologic trigger associated
with spontaneous regression of HCC.

Conclusion

Spontaneous regression of HCC is rarely reported. Its
coincidental course with anti-HCV therapy and HCV eradication,
however, is new and yet unexplained. Further observational data
and analysis of patients with spontaneous regression of HCC are
required to build a clinical significance and potentially guide
future growth of novel treatment strategies for HCC.